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(Received for publication, October 11, 1994 ) From the
Retinoic acid receptors (RARs) regulate gene expression either
by directly binding to the RAR-responsive elements or by antagonizing
the action of c-Jun/c-Fos (AP1). AP1 is involved in the expression of
metalloproteases, cytokines and other factors which play critical roles
in the turnover of extracellular matrix, inflammation and
hyperproliferation in diseases such as psoriasis, rheumatoid arthritis
and in tumor metastases. We demonstrate here that synthetic retinoids
inhibit 12-O-tetradecanoylphorbol-14-acetate-induced
transcription from the stromelysin AP1 motif through RAR All-trans-retinoic acid (RA) (
Figure 3:
AGN 190168 inhibits the endogenous
expression of stromelysin-1 in primary human foreskin keratinocytes.
Analysis of stromelysin-1 mRNA (A) and
glyceraldehyde-3-phosphate dehydrogenase mRNA (B) in control
(mock-treated, upperpanel in A and B) and AGN 190168-treated (lowerpanel in A and B) primary foreskin keratinocytes was performed
by RT-PCR. Total RNA from mock-treated and AGN 190168-treated
keratinocytes was reverse transcribed using oligo dT) and PCR-amplified
using stromelysin-1 and glyceraldehyde-3-phosphate dehydrogenase
primers. Samples (10 µl) were removed from PCR reaction at three
cycle intervals (as indicated in the figure), electrophoresed on 2%
gel, and analyzed by ethidium bromide staining. The rightmost lane in A and B is the DNA marker
lane.
Figure 1:
Retinoids selective for
transactivation through RAR
Figure 2:
Retinoids selective for transactivation
through RAR
AP1 and RARs are effectors of the opposite pathways of cell
proliferation and
differentiation(3, 16, 17, 18, 19) ,
and they mutually antagonize each other both at the level of
transactivation and DNA binding(7, 20) . The
involvement of the AP1 motif in RA-mediated negative regulation of
collagenase(6, 20, 21) ,
stromelysin(7) , TGF-
Volume 270,
Number 2,
Issue of January 13, 1995 pp. 923-927
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
(*)
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
, -
,
and -. Interestingly, these diaryl acetylenic retinoids, which are
potent agonists only for RAR
and RAR, but not for RAR
,
in transactivation assays, are able to inhibit AP1-dependent gene
expression through RAR. Thus these analogs can differentially
affect the transactivation and AP1 antagonistic functions of RAR.
These results demonstrate that the transactivation and AP1 antagonistic
functions are separable, and it should be possible to develop retinoids
that are completely specific for AP1 antagonism through all RARs.
Furthermore, using an RAR-selective ligand, we also demonstrate the
separation of ligand binding and AP1 antagonism functions of RARs.
)and its
synthetic analogs elicit their biological effects by binding to and
activating the RARs which belong to the steroid/thyroid receptor
superfamily(1, 2) . Three different RARs (,
, and ) have been identified(1, 2) , which,
upon ligand binding, regulate gene transcription either by activating
the expression of genes containing RAREs in their promoter regions (1) or by inhibiting the expression of certain genes by
antagonizing AP1 (c-Jun/c-Fos)-mediated gene expression(3) .
RARs contain two activation functions: AF-1, a ligand-independent A/B
region; and AF-2, a ligand-dependent E region transactivation
function(4, 5) . The regions of the RARs contributing
to the AP1 antagonism function are not identical to those involved in
transcriptional activation. The C-region of RAR
contains a major
ligand-dependent AP1 antagonism function (6) . (
)RARs are known to bind directly to RAREs(1) , and
this protein-DNA interaction is obligatory for ligand induced
transcriptional activation of responsive genes. However, RARs do not
bind to the AP1 response element in vitro(7) . Thus,
RARs may antagonize AP1 function by binding (directly or indirectly) to
c-Jun/c-Fos to form an inactive complex or may interact with and
sequester another nuclear accessory factor that is required for
AP1-mediated transcriptional activation(3) . Given the observed
differences in the regions of the RARs associated with transcriptional
activation and AP1 antagonism, it is possible that the structural
features of the RARs required for the protein-DNA interactions leading
to transcriptional activation may be somewhat different from those
required for the protein-protein interactions involved in AP1
antagonism. We report here the pharmacological separation of
transactivation and AP1 antagonism functions of RAR using
synthetic retinoid analogs. We demonstrate that analogs that
selectively transactivate through RAR and RAR and only weakly
through RAR
are potent inhibitors of AP1 function through
RAR. These results indicate that it should be possible to develop
retinoids that are completely specific for AP1 antagonism through all
RARs. Such retinoids may be of considerable clinical utility, since
they should be effective in treating hyperproliferative and
inflammatory diseases with fewer toxic side effects resulting from the
activation of retinoid-responsive genes. Furthermore, using a stilbene
synthetic retinoid analog, we demonstrate that although ligand binding
is obligatory for AP1 antagonism, ligand binding, and AP1 antagonism
are also independent properties of RARs.
Recombinant Plasmids
Expression vectors for RAR
and RXR (, , and ) as well as recombinant baculoviruses
containing RAR
, -, and - cDNAs have been described
previously(8, 9) . ERE-tk-CAT and estrogen receptor
(ER)-RAR expression vectors have been
described(10, 11) . The TPA-responsive reporter
containing an AP-1 sequence of the rat stromelysin-1 promoter (84S-CAT)
has been reported (7) .
Transfection of Cells and CAT Assay
For chimeric
receptor transactivation assays, HeLa cells grown in Dulbecco's
modified Eagle's medium containing 10% fetal bovine serum (FBS)
were transfected using the cationic liposome-mediated transfection
procedure. Cells were plated 18 h before transfection at about 40%
confluence (50,000 cells/well) in a 12-well plate. Cells were
transfected with ERE-tk-CAT (0.5 µg) along with one of the ER-RAR
chimeric expression vectors (0.1 µg). Transfections were performed
by Lipofectin (2 µg/transfection, Life Technologies, Inc.), and the
cells were treated with retinoids 18 h post-transfection. The detailed
transfection procedure has been described(11) . For
holoreceptor transactivation assays, CV1 cells (5,000 cells/well) were
transfected with an RAR reporter plasmid 
MTV-TREp-LUC (50 ng)
along with one of the RAR expression vectors (10 ng) in an automated
96-well format by calcium phosphate procedure(8) . For RXR
transactivation assays, an RXR-responsive reporter plasmid CRBP
II-TK-LUC (50 ng) along with one of the RXR expression vectors (10 ng)
was used(8, 9) . RXR-reporter contained DR1 elements
from human CRBP II promoter(1, 8) . A
-galactosidase (50 ng) expression vector was used as an internal
control in the transfections to normalize for variations in
transfection efficiency. The cells were transfected in triplicate for 6
h, followed by incubation with retinoids for 36 h, and the extracts
were assayed for luciferase and -galactosidase activities. The
detailed experimental procedure for holoreceptor transactivations has
been described(8, 9) . For retinoid-mediated AP1
antagonism assays, transfections were performed in HeLa cells using 0.6
µg of AP1-CAT and 0.08 µg of human RAR, -, and -
expression vectors, along with 2 µg of Lipofectamine (Life
Technologies, Inc.) for each well in a total volume of 500 µl. DNA
was precipitated with Lipofectamine for 30 min at room temperature
before transfer to cells. Five hours post-transfection, 500 µl of
Dulbecco's modified Eagle's medium containing 20%
charcoal-treated FBS was added. All the transfections were performed in
triplicate. Retinoids were added 18 h post-transfection, and 6 h later
the cells were treated with TPA (2 nM) to induce AP-1
activity. The next day after washing twice with phosphate-buffered
saline (without calcium and magnesium), the cells were harvested and
lysed for 60 min with occasional agitation using a hypotonic buffer
(100 µl/well) containing DNase I, Triton X-100, Tris-HCl, and
EDTA(11) . CAT activity was assayed in 50 µl of the lysed
cell extract using [
H]acetyl CoA (DuPont NEN) in
a 96-well plate. The CAT activity was quantified by counting the amount
of H-acetylated forms of chloramphenicol using a liquid
scintillation counter(11) .In Vitro RAR Binding Assays
For in vitro RAR binding experiments, baculovirus/Sf21 insect cell system was
used to express human RAR, -, and - as
described(9) . Suspension-grown Sf21 cells were infected with
the recombinant viruses at a multiplicity of infection of 2 for 48 h,
followed by disruption of the infected cells in 10 mM Tris, pH
7.6, 5 mM dithiothreitol, 2 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, and 0.4 M KCl as described (8, 9) . The binding assay contained 5-20 µg
of extract protein along with
[
H]all-trans-retinoic acid (5
nM) and varying concentrations (0-10 ;mz) of competing ligand in a 250-µl reaction. The binding
assays were performed as described previously(8, 9) .
PCR Amplification of Human Stromelysin-1 in Cultured
Keratinocytes
For the isolation of keratinocytes, fresh human
foreskins were washed in ethanol (70%) for 10 s followed by two
washings in keratinocyte growth medium (KGM, Clonetics). Foreskins were
cut into small pieces (4 mm diameter), incubated with trypsin (0.05%,
Life Technologies, Inc.) for 24 h at 4 °C, centrifuged (1,000 rpm)
for 6 min, filtered through a nylon mesh membrane, and cultured in KGM
containing 10% FBS. The media was replaced after 3 days with KGM
without FBS, and keratinocytes were maintained in serum-free media and
treated with AGN 190168 (1 µM) after three passages for 24
h. Total RNA was isolated from AGN 190168-treated and mock-treated
cultures by guanidine thiocyanate (Promega) method, reverse transcribed
using oligo(dT) and PCR-amplified using stromelysin-1 and
glyceraldehyde-3-phosphate dehydrogenase (internal control) primers.
Samples (10 µl) were removed from PCR reaction at three cycle
intervals (as indicated in Fig. 3), electrophoresed on 2% gel,
and analyzed by ethidium bromide staining. Stromelysin-1 primers:
5`-TGATGCTGTCAGCACTCTGAGGGG-3` and 5`-TCAACAATTAAGCCAGCTGTTACT-3`
amplified a 546-bp fragment. The rightmost lane in A and B is the DNA marker lane.
ODC Inhibition Assays
Ornithine decarboxylase
(ODC) activity inhibition by retinoids was determined in TPA-treated
female mice. Retinoids (5 mice/dose and 3 doses/experiment) were
applied dorsally in 100 µl of acetone 1 h prior to TPA treatment
(40 ng/mouse). ODC activity was measured in epidermal extracts obtained
4 h later and normalized to total epidermal protein
content(12) . The dose of retinoid (nM/mouse)
resulting in 80% inhibition of ODC activity was estimated in multi-dose
assays.
Synthetic Acetylenic Retinoids Are
RAR
The synthetic
acetylenic retinoids used in this study (see Table 1) are
RAR/-selective in Transactivation Assays
/-selective for transactivation since they activated the
expression of an estrogen receptor element reporter construct
(ERE-tk-CAT) in the presence of ER (ABC)-RAR
(DEF) and
ER(ABC)-RAR(DEF) but only weakly through ER(ABC)-RAR
(DEF) in
HeLa cells (Table 1). In these chimeric receptor assays, the DNA
binding domain was provided by the ER, whereas the transactivation was
retinoid-dependent by virtue of the presence of ligand binding domain
of RARs. Since the A/B region of RARs co-operate with their respective
AF-2s(4, 5) , we also determined the pattern of
transactivation of these retinoids using RAR holoreceptors. The RAR
/ selectivity of these analogs was maintained in the RAR
(
, , and ) holoreceptor transactivation assays (Table 2). AGN 191936 exhibited significant transactivation
through the RAR
and RAR holoreceptors. All of these
retinoids, except AGN 191936, were effective inhibitors of TPA-induced
ODC activity in hairless mouse skin (Table 1), thereby
demonstrating their anti-proliferation activity in an in vivo model. Since the promoter region of the ODC gene has a TPA and
c-Fos-responsive motif (13) , the inhibition of TPA-induced ODC
activity observed for these analogs probably reflects their ability to
inhibit c-Fos-dependent function through the complement of retinoid
receptors present in mouse skin. The binding affinities of the
retinoids were determined in vitro using baculovirus expressed
RAR
, -, and - (Table 2). Interestingly, most of
these analogs bound with reasonable affinity to all three RARs,
although they were ineffective transactivators through RAR
.
Furthermore, all the retinoids examined were RAR-specific and neither
bound (K
> 10 ;mz) to
baculovirus produced RXR
, -, and - (data not shown) nor
transactivated an RXR-responsive promoter construct (human CRBP II
promoter DR1 elements) in the presence of RXR expression vectors (Table 2). An RAR-selective pan-agonist, TTNPB (p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl]benzoic
acid) was used as a positive control in the holoreceptor
transactivation and binding assays (Table 2).
Separation of Transactivation and AP1 Antagonism
Properties of RAR
We used a stromelysin-1 promoter
construct (84S-CAT, carrying -84 to +6 base pairs of the rat
stromelysin-1 promoter) containing an AP1 motif as its sole enhancer
element (7) to study the antagonism of AP1-mediated gene
expression by these retinoids through each RAR subtype. RA inhibited
the TPA-induced expression of 84S-CAT through RAR, -, and
- in a dose-dependent manner in HeLa cells (Fig. 1A). Open bars represent inhibition of
84S-CAT expression by the addition of retinoids without any transfected
receptor expression vector. Similarly, retinoid analogs that were
selective for RAR
/ in transactivation assays, ester AGN
190168, and its acid derivative AGN 190299 also inhibited 84S-CAT
expression in a dose-dependent manner through RAR
, -, and
- (Fig. 1, B and C). These results
demonstrate that even though these retinoids do not effectively
activate gene expression through RAR
(Table 1), they still
can antagonize the AP1-dependent expression of 84S-CAT through RAR
in a potent manner. In contrast, AGN 191936, which was a poor inhibitor
of ODC activity (Table 1), did not significantly inhibit the
TPA-induced activity of 84S-CAT through RARs (Fig. 1D).
To rule out the possibility that RAR-mediated AP1 antagonism is
unique to these three retinoids, we analyzed four more RAR
/-selective retinoids from the same diaryl acetylenic
structural class (AGN 190121, 191554, 191636, and 191639) for mediating
AP1 antagonism through RAR
. All these retinoids down-regulated the
expression of 84S-CAT through RAR in a dose-dependent manner (Fig. 2) and with different potencies. IC values
for RAR
-mediated AP1 antagonism (50% inhibition of 84S-CAT
expression) for AGN 190121 was <1 nM. AGN 191554, 191636,
and 191639 were less potent with IC values of 20, 36, and
17 nM, respectively. These results demonstrate that the
acetylenic analogs that selectively transactivate through
RAR
/ are still capable of antagonizing the AP1-dependent gene
expression through RAR
. All the synthetic retinoids with AP1
antagonism activity were also potent inhibitors of ODC activity in
vivo (Table 1). All the synthetic retinoids, being
RAR-specific, did not significantly inhibit AP1-dependent gene
expression through RXR, -, and - (Table 2).
/ inhibit the expression of
84S-CAT through all RARs. Each panel shows the percent inhibition in
the expression of 84S-CAT without (open bars) or with
transfected RAR
(dark bars), RAR (striped
bars), or RAR (gray bars) in the presence of RA (A), AGN 190168 (B), AGN 190299 (C), and
191936 (D). Inhibition values are relative to the CAT activity
obtained during transfection of HeLa cells with the reporter and the
receptor constructs but in the absence of ligand. Transfections were
performed by Lipofectamine (2 µg/transfection, Life Technologies,
Inc.) and the variations in transfection efficiency did not exceed more
than 15% as adjudged by transfection with a
-galactosidase
expression vector pCH110 (Pharmacia Biotech Inc.). Retinoids were added
18 h post-transfection, and 6 h later cells were induced with TPA(2
nM). Cells were harvested after an additional 15 h of
incubation, and CAT activity was measured by scintillation counting.
All the experiments were performed in triplicate, and standard
deviation of the mean is indicated.
/ antagonize AP1 action through RAR
. Each
panel shows the percent inhibition in CAT activity after TPA-induction
of 84S-CAT by increasing concentrations of the retinoid either without (open bars) or with human RAR (dark bars),
relative to CAT activity observed in the absence of retinoids. 84S-CAT
(0.6 µg) was transfected in HeLa cells with or without human
RAR (0.08 µg) expression vector in the presence of AGN 190121 (A), 191554 (B), 191636 (C), and 191639 (D). Transfections were performed by Lipofectamine, all the
experiments were performed in triplicate, and the standard deviation of
the mean at each concentration of the retinoid is
indicated.
Ligand Binding to RARs Alone Is Not Sufficient for AP1
Antagonism
The stilbene retinoid analog AGN 191936 also
exhibited an interesting profile of activity. It bound effectively to
all three RARs in vitro (Table 2) and transactivated in
an RAR/-selective manner through the holoreceptors (Table 2) but did not significantly inhibit AP1-dependent gene
expression through any of the RARs (Fig. 1D). Thus, AGN
191936 is an example of a compound that can transactivate but not
inhibit AP1 function, again demonstrating that these functions are
separable. AGN 191936 is also a relatively ineffective inhibitor of ODC
activity, probably reflecting its inability to inhibit AP1 function.
Interestingly, AGN 191936 did not transactivate through the chimeric
receptors (Table 1), suggesting that A/B region-based AF-1 is
required for transactivation for this compound. Since AGN 191936 bound
to all three RARs (Table 2) but did not inhibit AP1-dependent
gene expression through RARs (Fig. 1D), these results
indicate that although ligand binding is mandatory for AP1 antagonism,
ligand binding and AP1 antagonism are also separate functions of RARs.
Biological Implications
These acetylenic retinoids
were also found to be active in a variety of biological assays of
anti-proliferation, cytokine production and metalloproteinase
expression. Since ODC is constitutively active during cell
transformation and it is a key regulator of the biosynthesis of
polyamines, which are required for cell proliferation(14) ,
inhibition by these compounds of ODC activity in hairless mouse skin
demonstrates anti-proliferative activity, which may be of relevance to
therapeutic use in diseases such as psoriasis. Indeed, AGN 190168 has
been shown to be effective in topical treatment of psoriasis in a
clinical trial (15) . Two of these compounds (AGN 190299 and
AGN 190121) were tested and shown to be effective (data not shown) in
other models of anti-proliferation (B-cell myeloma and cervical
carcinoma cell growth). Furthermore, AGN 190168 was a potent inhibitor
of endogenous stromelysin-1 gene expression in cultured human
keratinocytes (Fig. 3) and of endogenous IL-6 production in
lesionally derived Kaposi's sarcoma (KS) cells (data not shown). 1(22), and human papillomavirus 18
regulatory regions (23) has been documented. RA also inhibits
the expression of IL-6(24) , which is TPA-inducible and
contains an AP1 motif in its promoter region(25) . IL-6 is
highly elevated in rheumatoid arthritis, psoriasis, and KS, and it is a
potent mitogen for KS cells(24, 26, 27) . The
elevation of metalloproteinases such as collagenase can contribute to
the pathogenesis of chronic inflammatory diseases such as rheumatoid
arthritis (3, 20) and tumor metastasis(28) .
Antagonism of AP1 action also explains RA inhibition of collagenase
production by fibroblasts, monocytes, and keratinocytes (29, 30, 31) and it may be the underlying
mechanism for the therapeutic effect of RA on photodamaged human skin (32) . Thus, the cross-talk between the retinoid and AP1 signal
transduction pathways could clearly be manipulated for therapeutic
benefit in inflammatory and hyperproliferative diseases as demonstrated
by the clinical utility of retinoids in treating psoriasis, acute
promyelocytic leukemia, premalignant dysplasias, and
KS(15, 33, 34, 35) . However, the
wider use of retinoids is often hampered by the toxicity associated
with retinoid therapy(36) . As to what complement of
therapeutic and toxic effects are associated with the AP1 antagonism or
transcriptional activation properties of retinoids remains unknown and
could effectively be determined only by the development of analogs that
are specific for each pathway. Our demonstration that AP1 antagonism
and transactivation are separable functions of RAR suggests that
the synthesis of retinoids with only AP1 antagonism properties is
possible. Such retinoids might have greatly improved therapeutic:toxic
ratios in the treatment of inflammatory and hyperproliferative
disorders. A similar strategy could be applied to glucocorticoids,
which also antagonize AP1 and are potent anti-inflammatory molecules
with serious side effects.
))
We thank R. Heyman for RAR and RXR expression vectors,
MTV-TRE
-LUC and CRBP II-TK-LUC; P. Chambon for
84S-CAT; M. Pfahl for ER-RAR chimeras and ERE-tk-CAT; D. W. Gil, T.
Breen, and T. Arefieg for chimeric transactivations; C. Suto for
holoreceptor transactivations; D. Mais for RAR binding; S. Patel for
RXR antagonism; S. Thacher and S. Friant for cultured human primary
foreskin keratinocytes; and T. Arefieg for ODC assays. We also thank S.
Thacher and E. Klein for critical review of the manuscript.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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D. DiSepio, M. Malhotra, R. A. S. Chandraratna, and S. Nagpal Retinoic Acid Receptor-Nuclear Factor-Interleukin 6 Antagonism. A NOVEL MECHANISM OF RETINOID-DEPENDENT INHIBITION OF A KERATINOCYTE HYPERPROLIFERATIVE DIFFERENTIATION MARKER J. Biol. Chem., October 10, 1997; 272(41): 25555 - 25559. [Abstract] [Full Text] [PDF]
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 M. Shibakura, T. Koyama, T. Saito, K. Shudo, N. Miyasaka, R. Kamiyama, and S. Hirosawa Anticoagulant Effects of Synthetic Retinoids Mediated Via Different Receptors on Human Leukemia and Umbilical Vein Endothelial Cells Blood, August 15, 1997; 90(4): 1545 - 1551. [Abstract] [Full Text] [PDF]
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 S. M. Thacher, A. M. Standeven, J. Athanikar, S. Kopper, O. Castilleja, M. Escobar, R. L. Beard, and R. A. S. Chandraratna Receptor Specificity of Retinoid-Induced Epidermal Hyperplasia: Effect of RXR-Selective Agonists and Correlation with Topical Irritation J. Pharmacol. Exp. Ther., August 1, 1997; 282(2): 528 - 534. [Abstract] [Full Text]
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 B. M. Vayssière, S. Dupont, A. Choquart, F. Petit, T. Garcia, C. Marchandeau, H. Gronemeyer, and M. Resche-Rigon Synthetic Glucocorticoids That Dissociate Transactivation and AP-1 Transrepression Exhibit Antiinflammatory Activity in Vivo Mol. Endocrinol., August 1, 1997; 11(9): 1245 - 1255. [Abstract] [Full Text]
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E. Guerin, M.-G. Ludwig, P. Basset, and P. Anglard Stromelysin-3 Induction and Interstitial Collagenase Repression by Retinoic Acid. THERAPEUTICAL IMPLICATION OF RECEPTOR-SELECTIVE RETINOIDS DISSOCIATING TRANSACTIVATION AND AP-1-MEDIATED TRANSREPRESSION J. Biol. Chem., April 25, 1997; 272(17): 11088 - 11095. [Abstract] [Full Text] [PDF]
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A. Scafonas, C. L. Wolfgang, J. L. Gabriel, K. J. Soprano, and D. R. Soprano Differential Role of Homologous Positively Charged Amino Acid Residues for Ligand Binding in Retinoic Acid Receptor alpha Compared with Retinoic Acid Receptor beta J. Biol. Chem., April 25, 1997; 272(17): 11244 - 11249. [Abstract] [Full Text] [PDF]
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A. N. Fanjul, D. Delia, M. A. Pierotti, D. Rideout, J. Qiu, and M. Pfahl 4-Hydroxyphenyl Retinamide Is a Highly Selective Activator of Retinoid Receptors J. Biol. Chem., September 13, 1996; 271(37): 22441 - 22446. [Abstract] [Full Text] [PDF]
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C. Agarwal, R. A. S. Chandraratna, A. T. Johnson, E. A. Rorke, and R. L. Eckert AGN193109 Is a Highly Effective Antagonist of Retinoid Action in Human Ectocervical Epithelial Cells J. Biol. Chem., May 24, 1996; 271(21): 12209 - 12212. [Abstract] [Full Text] [PDF]
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 C. Fisher, M. Blumenberg, and M. Tomic-Canic Retinoid Receptors and Keratinocytes Critical Reviews in Oral Biology & Medicine, January 1, 1995; 6(4): 284 - 301. [Abstract] [Full Text] [PDF]
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